Project Summary The emergence of drug resistant bacterial strains creates a real possibility that more infectious diseases will become untreatable in the near future. As a striking example, it is estimated that 30-40% of extensively drug resistant tuberculosis (XDR-TB) is now untreatable. Because of this, new approaches to treating drug resistant bacteria, including TB, are urgently needed. In this proposal we explore a highly active pharmacophore product which has improved and potent activity on dormant Mycobacterium tuberculosis (Mtb) relative to actively dividing Mtb. This proposal describes the design, synthesis, and study of a lead pharmacophore derived from a marine natural. We propose to develop an effective chemical synthesis to facilitate hit-to-lead development and the identification of biochemical targets. The project will use phenotypic screening as the basis for improving the in vitro inhibitory profile. Hits will be validated using orthogonal assays. The results from these studies will be used to advance our knowledge of the active pharmacophore to produce a new drug lead for killing Mycobacterium tuberculosis. The molecular target of this class of compounds will be elucidated and characterized. This research program brings together a complementary team of two PIs with expertise related to the screening, synthesis and characterization of new compounds to treat Mtb. The investigators are from the University of Toledo and University of Central Florida.